Human hemoglobin production is regulated during development by the coordinate and sequential expression of two multigene families located on chromosomes 11 and 16. The switch between fetal and adult hemoglobin production results from the inactivation of the paired gamma globin genes and activation of the beta globin gene. This switch is impaired in a number of conditions termed hereditary persistence of fetal hemoglobin (HPFH). One class of HPFH variants are due to single base changes in the gamma globin gene promoters and upstream sequences. Our work in the last granting period has been focused on determining the mechanism for high gamma globin gene expression resulting from single base changes at position -202 of the G gamma globin gene. Our studies have revealed that a ubiquitous factor binds at this position and possibly serves to repress gamma globin gene expression. In the current proposal, we plan to further characterize this factor, determine its role in affecting the assembly of the transcriptional complex of the gamma globin gene promoter, and determine the possible interaction f the gamma globin gene transcriptional complex with other elements in the globin gene domain, especially the 3' gamma globin gene enhancer and the Locus Control Region. These studies are intended to determine the biochemical mechanisms that regulate gamma globin gene expression, and to develop new concepts that may lead to a modification of gamma globin genes in adults.